GEA-NUS Pharmaceutical Processing Research Laboratory, Department of Pharmacy, National University of Singapore, 18 Science Drive 4, Singapore, 117543, Singapore.
Research and Development, Roquette Asia Pacific Pte. Ltd., 11 Biopolis Way, Helios #05-06, Singapore, 138667, Singapore.
AAPS PharmSciTech. 2018 May;19(4):1860-1868. doi: 10.1208/s12249-018-0999-y. Epub 2018 Apr 10.
The precipitation inhibitory effect of cellulosic polymers in relation to their physicochemical properties was studied. Using a poorly water-soluble model drug, griseofulvin, the precipitation inhibitory effect of a series of hydroxypropyl methylcellulose (HPMC) and methylcellulose polymers was studied using solvent-shift method. The extent of supersaturation maintenance of each polymer was then quantified by the parameter, supersaturation factor (SF). Partial least square (PLS) regression analysis was employed to understand the relative contribution from viscosity, hydroxypropyl content (HC), methoxyl content, methoxyl/hydroxypropyl ratio, and drug-polymer interaction parameter (χ) on SF. All grades of cellulosic polymers effectively prolonged supersaturation of griseofulvin. PLS regression analysis revealed that HC and χ appeared to have the strongest influence on SF response. A regression model of SF = 1.65-0.16 χ + 0.05 HC with a high correlation coefficient, r of 0.921, was obtained. Since the value of χ is inversely related to the strength of drug-polymer interaction, the result shows that SF increases with increasing drug-polymer interaction and increasing HC. As such, it can be implied that strong drug-polymer interaction and presence of hydroxypropyl groups in cellulosic polymers for hydrogen bonding are two key parameters for effective supersaturation maintenance. This knowledge on the relative contribution of polymer physicochemical properties on precipitation inhibition will allow the selection of suitable cellulosic polymers for systematic development of supersaturating drug delivery systems.
研究了纤维素聚合物与其物理化学性质的沉淀抑制效果。使用一种水溶性较差的模型药物灰黄霉素，采用溶剂转移法研究了一系列羟丙基甲基纤维素（HPMC）和甲基纤维素聚合物的沉淀抑制效果。然后通过过饱和度因子（SF）定量评估每种聚合物维持过饱和度的程度。偏最小二乘（PLS）回归分析用于理解粘度、羟丙基含量（HC）、甲氧基含量、甲氧基/羟丙基比以及药物-聚合物相互作用参数（χ）对 SF 的相对贡献。所有等级的纤维素聚合物都能有效地延长灰黄霉素的过饱和度。PLS 回归分析表明，HC 和 χ 似乎对 SF 响应有最强的影响。得到了一个具有高相关系数 r 为 0.921 的 SF = 1.65-0.16 χ + 0.05 HC 的回归模型。由于 χ 的值与药物-聚合物相互作用的强度成反比，结果表明 SF 随药物-聚合物相互作用的增强和 HC 的增加而增加。因此，可以推断出纤维素聚合物中药物-聚合物相互作用较强和存在羟丙基基团进行氢键是有效维持过饱和度的两个关键参数。关于聚合物物理化学性质对沉淀抑制相对贡献的这一知识将允许选择合适的纤维素聚合物用于系统开发超饱和药物传递系统。
